ASSURE: Effect of an Oral Agent Inducing Apo A-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study

Background

Recent intervention studies with synthetic HDL-c particle and recombinant Apo A-I have shown that HDL has the capacity to reverse the process of coronary atherosclerosis. The most important component of HDL-c consists of Apo A-I. Increasing Apo A-I levels most likely has a beneficial effect on atherosclerotic plaque stability and size, and on cardiovascular disease.
RVX-208 is a member of a new class of small molecules who are candidates for the treatment of dyslipidaemia, by increasing HDL-c plasma levels through enhanced Apo A-I transcription.
De ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE) study maps the effect of increasing Apo A-I synthesis with RVX-208, on coronary atherosclerotic disease, when this is administered in addition to standard therapy, in patients with coronary artery disease and low HDL-c levels, as measured by intravascular ultrasound (IVUS).

Main results

A numerical, but not statistically significant reduction of the percentage atheroma volume (PAV) was seen as compared to baseline, after treatment with RVX-208 vs. placebo (-0.40 vs. -0.30 %, P=0.81).

ALAT/ASAT>3x ULN occurred more often in the RVX-208 group (7.1%) than with placebo (0%, P=0.009).

Conclusion

Treatment with RVX-208 had no statistically significant effect on the atherosclerotic plaque. A trend towards regression of the plaque was however seen after RVX-208. Although RVX-208 was developed hoping that it would be a potent oral agent, this is not the case.
It should be noted that the placebo group performed extremely well: good biochemical changes were seen. This underlines the importance of good treatment; patients were seen very frequently in this study.
Considering earlier promising results, these findings are disappointing and unexpected. Dr. Nicholls said at the ESC Congress that these results should not be interpreted as evidence that the hypothesis is not correct that increasing HDL-c give cardiovascular benefits. RVX-208 is the first epigenetic attempt to metabolically treat cardiovascular disease. Ongoing research will investigate the cardiovascular efficacy of other agents that target HDL-c.
Previous experimental studies with RVX-208 were promising. But it is a long way from cell studies, via animal models, to humans. Although the HDL-c hypothesis has not been confirmed, this still seemed a good idea. Dr. Nicholls had to conclude that turned out to be a neutral study and that it has not expanded our knowledge on the HDL-mechanism.